Metabolic syndrome is a disorder of energy utilization and storage characterized by obesity, high serum triglycerides and low high-density lipoprotein (HDL) plasma levels. Individuals with metabolic syndrome have essentially twice the risk of developing cardiovascular disease (CVD) and Type 2 diabetes mellitus (T2D), compared to those without the syndrome. In the search for improved and novel therapeutic strategies, we have recently demonstrated that miRNAs plays an important role during the progression of this disease. In particular, work from our group and others identified miR-33a and miR-33b as key regulators of major components of metabolic syndrome, namely high triglycerides, low HDL, and insulin resistance. To investigate in depth the molecular mechanism by which miR-33a and miR-33b regulate glucose and lipid metabolism, we have recently developed two unique mouse models: miR-33a deficient mice (miR-33a-/-) and humanized SREBP1 mice that contain the miR-33b sequence (miR-33bKI). Using cutting-edge techniques, we will identify the regulatory network through which miR-33a and miR-33b regulate lipid metabolism both in vitro and in vivo, and assess the potential therapeutic value of anti-miR-33a and anti- miR-33b therapy for the treatment of cardiometabolic diseases including atherosclerosis and metabolic syndrome.